Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula: is approved, under the trademark Zoloft®, by the U.S. Food and Drug Administration, as a serotonin re-uptake inhibitor for the treatment of depression, obsessive-compulsive disorder, panic disorder and post-traumatic disorder. In the solid state, sertraline hydrochloride exists in various crystalline forms having different physical properties.
The present invention relates to the solid state physical properties, i.e., polymorphism, of sertraline hydrochloride. These properties may be influenced by controlling the conditions under which sertraline hydrochloride is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account when developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences because it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by powder X-ray diffraction, solid state 13C NMR spectrometry and infrared spectrometry.
A solid form (polymorph) of sertraline hydrochloride is disclosed for example in WO 01/90049, which is directed to amorphous form of sertraline hydrochloride. The solid state chemistry of sertraline hydrochloride is also disclosed in JP 0026378 and JP 0026379. According to the English abstract of JP 0026379, “a sertraline free base is dissolved in a solvent (e.g. an ester-based organic solvent such as ethyl acetate, butyl acetate or the like or a ketone-based organic solvent such as acetone, methyl isobutyl ketone or the like) or a sertraline organic acid salt is suspended in a solvent, and hydrochloric acid or hydrogen chloride is introduced into the solution or suspension preferably at a room temperature or the reflux temperature of the solvent to give sertraline hydrochloride crystal of metastable form. The amount of the hydrochloric acid or hydrogen chloride used is preferably 1.0-5.0 mol based on 1.0 mol of the sertraline free base or the organic salt.”
U.S. Pat. No. 4,536,518, incorporated herein by reference, describes a synthesis of sertraline hydrochloride. U.S. Pat. No. 5,248,699, incorporated herein by reference, describes five crystalline forms of sertraline hydrochloride, designated Form I, Form II, Form III, Form IV and Form V. These and additional forms of sertraline hydrochloride are also disclosed in U.S. Pat. Nos. 6,452,054, 6,495,721 and 6,500,987, incorporated herein by reference.
U.S. Pat. No. 4,536,518 (“the '518 patent”) describes the preparation of sertraline hydrochloride with a melting point of 243-245° C. by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. The solid state properties of the sertraline hydrochloride so produced are not otherwise disclosed.
According to U.S. Pat. No. 5,248,699 (“the '699 patent”), the sertraline hydrochloride produced by the method of the '518 patent has a crystalline form denominated “Form II”. The method described in the '699 patent for making Forms II and IV is by the rapid crystallization of sertraline hydrochloride from an organic solvent. An actual example is not provided.
The '699 patent discloses that Forms II, III, IV and V are metastable, and that granulation of Forms II, III or IV in isopropyl alcohol, ethyl acetate, hexane at a temperature of 40° to 60° C. causes conversion to Form I.
The preparation of sertraline hydrochloride Form II is also disclosed in WO 01/32601. In Examples 9-12, sertraline hydrochloride Form II is prepared from a maximum of 50 grams of sertraline free base in solution. The specification further discloses regarding Form II: “Sertraline hydrochloride polymorphic form II may be formed from a solution of sertraline free amine with some seeding crystals of form II before the addition of a solution of hydrogen chloride; or from a stirred suspension of sertraline hydrochloride polymorphic form V with some seeding crystals of sertraline hydrochloride polymorphic form II; or by drying a sertraline hydrochloride alcohol solvate at temperatures from about 0 to 30° C. in high vacuum (<1 mbar); or from stirred suspensions of sertraline hydrochloride polymorphic form CSC1, CSC2 or T1 with some seeding crystals of sertraline hydrochloride polymorphic form II. Furthermore, Sertraline hydrochloride polymorphic form II may be formed according to a process, wherein a solution of sertraline free amine is seeded with some crystals of polymorphic form II and a solution of hydrogen chloride is added.”
WO 02/096859, also discloses processes for preparation of sertraline hydrochloride Form II. In the examples, sertraline hydrochloride is prepared from a maximum of 40 grams of sertraline mandelate salt; after obtaining a solution of the free base in isopropanol, hydrogen chloride in ethyl acetate is added at a controlled rate to obtain the hydrochloride salt.
There is a need in the art for preparation of sertraline hydrochloride Form II substantially free of other polymorphic forms of sertraline hydrochloride, particularly on an industrial scale.